The norepinephrine transporter (NET) protein found within peripheral and central nervous system (CNS) tissues is responsible for the clearance of the endogenous neurotransmitter norepinephrine (NE) from the synaptic cleft after neuronal firing. Chemical agents that inhibit NE synaptic clearance (reuptake) by the NET by binding at the NET (inhibitor binding) serve to enhance NE synaptic concentrations. The CNS biomedical literature describes that NET inhibitor drugs and related agents that enhance NE synaptic concentrations are indicated with anti-anxiety, antidepressant, and improved cognitive qualities [Millan 2006]. Additionally, NET interacting inhibitor-based binding drugs and similar ligands, have the ability to alter the perception of pain [Millan 2006] and influence the outcomes of attention deficit disorders, post traumatic stress disorder (PTSD), and related co-morbid psychiatric states through the modulation of NE neurotransmission within the CNS [Rommelfanger 2007, Bonish 2006, Stone 2005, Cannistraro 2003, Millan 2000].
Examples of CNS NET inhibitor binding drugs include desipramine, (S,S)-reboxetine, atomoxetine, and (S)-duloxetine [Mandela 2006, Millan 2006, Hajos 2004, Zhou 2004, Bymaster 2002]. The drugs are thought to promote some of their beneficial effects by modulating NE synaptic concentrations by blocking reuptake of NE at NET. Effective compositions of the drugs include salts; for example, with duloxetine as the hydrochloride (HCl) salt. The drugs are characterized with in vitro pharmacological NET inhibitor competitive binding affinities (Ki value) in the moderate to low nanomomolar concentration range. Many of the established NET inhibitor binding drugs and agents also possess cross binding interactions with other CNS target proteins; defining them with NET non-selective binding profiles. In particular, the other cross binding interactions include the serotonin transporter (SERT) and the dopamine transporter (DAT) [Mandela 2006, Millan 2006] proteins.
Drugs and ligands that are highly selective for and potent at NET are considered as potential CNS therapeutics [Millan 2006, Zhou 2004, Bymaster 2002] for certain NE-based psychiatric disorders and diseased states. Structurally novel NET inhibitor agents devoid of promiscuous CNS binding (e.g., SERT and/or DAT interactions, amongst other sites) are few. Examples of NET potent and selective agents include stereochemical forms of ligand nisoxetine [Tejani-Butt 1992], which when labeled with a radioactive atom such as tritium ([3H]) are capable of the quantitative detection of NET in tissues [Smith 2006, Tejani-Butt 1992 & 1993].
Pharmacologically potent and selective NET inhibitor agents which are appended with select positron emitting radionuclide atoms (e.g., carbon-11, fluorine-18, bromine-76, iodine-122, iodine-124, iodine-131) at select locations on the chemical structures, can serve as quantitative positron emission tomography (PET) imaging tracers for the NET target protein in live brain [Ding 2006 & 2005, Logan 2007 & 2005]. Examples include the NET PET imaging tracers (S,S)-[11C]MeNER and (S,S)-[18F]FMeNER which have chemical structures possessing two aromatic ring moieties joined by a heteroatom linkage [Ding 2006 & 2005, Seneca 2006, Schou 2004 & 2003]. Examples of NET PET imaging tracers capable of detecting and quantifying NET protein density in a reproducible manner within discrete tissue regions (for example within brain) are limited [Logan 2007 & 2005, Ding 2006, Seneca 2006]. Similarly, NET inhibitor agents appended with other radionuclides (for example, iodine-123) may serve as single photon emission computed tomography (SPECT) imaging agents [Tamagnan 2007].
Structurally novel NET PET and SPECT imaging tracers, that are defined as classes of compounds with demonstrated in vitro NET binding selectivity and potency, are useful for the detection and quantification of NET by in vivo and in vitro methods within the clinic and laboratory [Logan 2007 & 2005, Smith 2006, Tejani-Butt 1992 & 1993]. Since select CNS disorders and diseases are thought to be a result of abnormalities associated with NET or the NE system, then detection and quantification of NET in select tissues provides a method for diagnoses [Logan 2007 & 2005]. The detection of NET and the determination of altered tissue NET density (concentration) in regions of interest (ROIs) by in vivo PET imaging, and related in vitro tracer methods [Smith 2006, Tejani-Butt 1992 & 1993], can be indicative and diagnostic of select CNS diseases, disorders, and abnormalities resultant from NET or NE pathway dysregulations.
For example, with brain tissues the detection and quantification of NET by dynamic tissue imaging methods provides a means for the diagnosis of select neuropathologies [Tejani-Butt 1992 & 1993, Logan 2007 & 2005, Ding 2006 & 2005] and mental health disorders, not limited to neurodegenerative conditions, anxiety, depression, attention deficit disorders, drug dependency, post traumatic stress disorder, among others [Rommelfanger 2007, Ding 2006 & 2005, Vieweg 2006, Klimek 1997, Ordway 1997]. Additionally, with a NET PET tracer NET target protein occupancy of other non-radioactive NET inhibitor drugs and agents [Logan 2007, Seneca 2006] may be assessed. For example, the analysis by quantitative imaging of competitive NET binding between a tracer and non-radioactive drug or agent provides an understanding of in vivo dynamic competitive NET binding and pharmacokinetic performance of agents within tissues (including brain) over time [Logan 2007, Ding 2006, Seneca 2006, Schou 2004 & 2003, Tamagnan 2007].
All patents, patent applications, provisional patent applications and publications referred to or cited herein, are incorporated by reference in their entirety to the extent they are not inconsistent with the teachings of the specification.